In:
Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 2727-2727
Kurzfassung:
Nucleophosmin 1 (NPM1) is the most common gene mutated in acute myeloid leukemia (AML). Several putative mechanisms for the role of NPM1 in the generation of AML have been proposed, including acting as a tumor suppressor by promoting the degradation of p53 and sequestration of wild-type NPM1. However, the specificity of the mutation- most commonly a 4 base pair duplication in the C-terminus- suggests that it may be a gain- of- function mutation conferring an unidentified pro-leukemic effect. Using a novel set of leukemia cell lines generated with CRISPR/Cas9 technology in combination with studies in primary hematopoietic cells, we show that mutant NPM1 may promote leukemia by deregulating protein translation with downstream effects on cellular metabolism. Thus, mutant NPM1 may serve as a critical lynchpin to match metabolic precursors and cellular energetics to ribosomal output. The implications of our results suggest that combined metabolic and protein translation inhibition may be a previously unidentified vulnerability in AML with mutated NPM1. CRISPR/Cas9 technology was used to generate a set of isogenic cell lines derived from the heterozygous OCI-AML3 line. Transcriptomic analysis of clones with either parental allele configuration (wild-type and mutant, WTAM) vs. inactivation of the mutant allele (wild-type only, WTO) confirmed that mutant NPM1 regulates HOX genes, as shown in both mouse models and patient samples. Next, the effects of mutant NPM1 on ribosome biogenesis and protein translation were assayed with pulse- chase and static experiments and showed both ribosomal RNA and protein translation were increased in WTAM clones vs. WTO clones. During these investigations, cell size was noted to be increased in WTAM cells. Cell size can be a consequence of the metabolic activity of a cell. Analysis of the rate of glucose consumption and lactate production showed that WTAM cells have increased aerobic glycolysis compared with WTO cells. To test if mutant NPM1 is sufficient to drive both protein translation and aerobic glycolysis in a normal cell, these studies were replicated in normal human hematopoietic stem cells stably expressing either wild-type NPM1 or mutant NPM1. In summary, our results suggest that mutant NPM1 acts through dysregulation of protein translation and participates in metabolic reprogramming required to drive oncogenic transformation. Disclosures No relevant conflicts of interest to declare.
Materialart:
Online-Ressource
ISSN:
0006-4971
,
1528-0020
DOI:
10.1182/blood.V128.22.2727.2727
Sprache:
Englisch
Verlag:
American Society of Hematology
Publikationsdatum:
2016
ZDB Id:
1468538-3
ZDB Id:
80069-7